Meeting Minutes - April 23, 2009

Office of AIDS Research Advisory Council 
Twenty-Eighth Meeting
April 23, 2009

National Institutes of Health
U.S. Department of Health and Human Services
5635 Fishers Lane Conference Center
Rockville, MD

Members Present: Dr. James W. Curran (Chair), Dr. Jack Whitescarver (Executive Secretary), Ms. Dawn Averitt Bridge, Dr. Coleen K. Cunningham, Dr. Sharon E. Frey, Dr. Gary W. Harper, Dr. Betsy C. Herold, Ms. Lynn Paige Nestor, Dr. Michael F. Summers, and Dr. Paul Volberding

Ex Officio Members Present: Dr. John G. Bartlett, Dr. Ralph J. DiClemente, Dr. Carl W. Dieffenbach, Dr. Kevin Fenton, Dr. Diana M. Lopez, Dr. Nelson L. Michael, and Dr. Christel H. Uittenbogaart

Invited Speakers and Guests: Dr. Adaora Adimora, Dr. Dolores Albarracín, Dr. Susan Allen, Dr. Jared Baeten, Dr. Shari L. Dworkin, Dr. Jessica E. Justman, Ms. Jennifer Klot, Dr. Nicolai Lohse, Dr. Jiri Mestecky, Dr. Charles S. Morrison, Dr. Lut Van Damme, and Dr. Charles R. Wira

Welcome and Meeting Overview

The National Institutes of Health (NIH) Office of AIDS Research Advisory Council (OARAC) convened its twenty-eighth meeting at 8:30 a.m. at the Fishers Lane Conference Center in Rockville, Maryland. Dr. James W. Curran, Chair, welcomed the OARAC members, invited speakers, and guests.

The topic of the meeting was HIV Prevention Research for Women. Dr. Curran noted the importance of HIV prevention and the need to empower women in the context of sexual behavior issues. He stated that experts in this field of research would present their work and their recommendations for future research priorities.

The minutes of the October 24, 2008 OARAC meeting were approved as submitted.

Director’s Report

Dr. Jack Whitescarver, Director of the Office of AIDS Research (OAR), welcomed everyone to this meeting of the OARAC. He also welcomed Dr. Ralph DiClemente as the newest ex officio member to the Council. Dr. DiClemente represents the National Institute of Mental Health’s National Advisory Mental Health Council. Dr. DiClemente is Charles Howard Candler Professor of Public Health and Associate Director for Prevention Sciences of the Emory/Atlanta Center for AIDS Research. He holds concurrent appointments as Professor in the Departments of Pediatrics, Medicine, and Psychiatry at the Emory University School of Medicine; and he also serves as Adjunct Professor at Morehouse School of Medicine.

Dr. Whitescarver provided an update on OAR’s actions to recent recommendations by OARAC. In follow up to OARAC’s October 2008 meeting on Genomics and HIV, OAR is working with several key ICOs to develop new programs. One of those initiatives will focus on human immunology which may target some of the topics that will be discussed at today’s meeting.

Dr. Whitescarver referred council members and guests to the summary of the Director’s Report in the meeting folder.

Conflict of Interest Statements

Dr. Whitescarver asked Council members to review and sign the conflict of interest statement provided to them. He reminded them that NIH policy requires all individuals appointed to serve as Advisory Council members to complete financial disclosure forms and that he is required to certify that all OARAC members have complied with this requirement.

Budget Overview

Dr. Whitescarver reported that the NIH budget approved for fiscal year (FY) 2009 includes a 2.8 percent increase over the FY 2008 budget. This increase is below the level of inflation. The FY 2010 budget exercise is delayed due to the recent change in the Administration. A substantial increase over FY 2009 funding levels is not expected. Dr. Whitescarver also stated that OAR is required annually to submit a by-pass budget directly to the White House. OAR also submits the by-pass budget to key members of appropriation committees in Congress. The FY 2010 by-pass budget requests a 15 percent increase over FY 2009 funding levels.

Dr. Whitescarver stated that the American Recovery and Reinvestment Act of 2009 (ARRA) provided $10.4 billion to NIH to be distributed in five categories: $8.2 billion for extramural scientific research; $1.0 billion for extramural construction through the National Center for Research Resources (NCRR); $0.5 billion for repair, improvement, and construction of Intramural research infrastructure; $0.3 billion for the Shared Instrumentation Grant Program (SIG) and other capital equipment; and $0.4 billion for comparative effectiveness research.

Dr. Whitescarver noted that the ARRA funds are required to be spent to create and preserve jobs and advance biomedical science; and spent in the U.S. within a 2 year time frame. Congress also requires a separate, publicly available, weekly accounting of the spending of all ARRA funds.

ACT Against AIDS Campaign Overview

Dr. Whitescarver stated that the White House recently announced the federally funded “ACT Against AIDS” public education and awareness campaign. Dr. Whitescarver asked Dr. Kevin Fenton, Director of the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention at the U.S. Centers for Disease Control and Prevention (CDC) to provide an overview of the campaign.

Dr. Fenton stated that the ACT Against AIDS kick-off phase, called “9 ½ Minutes,” began April 7, 2009 at a White House press conference. The ACT Against AIDS campaign ties together existing and planned acquired immunodeficiency syndrome (AIDS) campaigns, as well as efforts to mobilize community leaders under one campaign. ACT Against AIDS will provide a strategic framework for AIDS prevention activities over the next five years.

Dr. Fenton stated that the 9 ½ Minute campaign highlights the CDC estimate that every 9 ½ minutes, someone in the United States is infected with HIV. The campaign seeks to raise awareness of, and combat complacency toward, the domestic HIV/AIDS epidemic, and to increase information seeking behaviors. Communication tactics include online banner ads and videos, transit ads, airport dioramas, radio public service announcements, and campaign websites. Messages will be available in English and Spanish.

Dr. Fenton noted that the ACT Against AIDS campaign will target multiple audiences, including at-risk populations. The campaign is designed in phases to methodically and strategically match messages and delivery channels to specific objectives and audience segments. There are specific research and evaluation plans for each phase.

Dr. Fenton noted that the launch of the ACT Against AIDS campaign and the 9 ½ Minutes phase was successful in re-energizing traditional partners; mobilizing the African American community; and attracting extensive media coverage to reach targeted audiences. Dr. Fenton stated that over 23,000 users have signed up on the NineandaHalfMinutes.org website.

Dr. Fenton stated that the ACT Against AIDS Media Initiative establishes a coalition of entertainment, print, online, and other media organizations committed to disseminating campaign messages and materials. The initiative also will create partnerships with media organizations to develop their own campaigns that complement ACT Against AIDS. The Leadership Initiative includes a range of large, national African American organizations that have demonstrated success in community engagement, involvement, and leadership. An HIV coordinator will help mobilize the organizations and extend campaign messages within the organizations.

Dr. Fenton reviewed the status of the three ACT Against AIDS phases in development. The “MSM HIV Testing” phase will target men-who-have-sex-with-men (MSM), especially African American, Hispanic, and Latino MSM, and will focus on behavior change objectives. Online pilot testing for this phase will begin in April 2009. The “Take Charge. Take the Test.” phase will focus on behavior change objectives and will target African American women. The national roll-out for this phase will begin in June 2009. The “I Know” phase will target the general population of African American young people and will focus on education and health literacy objectives. Formative research and planning for this phase has begun and the launch is planned for June 2009.

Update on OARAC Working Groups for Treatment and Prevention Guidelines

Dr. John G. Bartlett, Professor of Medicine and Chief of Infectious Diseases at the Johns Hopkins University School of Medicine and Co-Chair of the Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, presented an update on the activities of the OARAC Working Groups for Treatment and Prevention Guidelines. He noted that all five of the Working Group guidelines are available on the Clinicalinfo website, https://clinicalinfo.hiv.gov/en/guidelines. Dr. Bartlett commented that the online guidelines on the use of antiretroviral therapy (ART) are updated about once a month due to the rapid emergence of new data.

Dr. Bartlett reported that the guidelines for treatment and prevention of opportunistic infections (OIs) in HIV-infected individuals are a collaborative effort among NIH, CDC, and the HIV Medicine Association of the Infectious Diseases Society of America. These guidelines are available in hard copy. He stated that an update to the Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents was released April 10, 2009.

Dr. Bartlett stated that a revision of the Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Exposed and HIV-Infected Children is in process and will be released within the next two months. The revision will include new information on the early diagnosis of HIV infection in infants; ART and management of OIs, including immune reconstitution inflammatory syndrome (IRIS); and new recommendations for childhood vaccines for HIV-infected children. The guidelines also address several new OIs including aspergillosis, bartonellosis, human herpes viruses 5, 7, and 8, malaria, and progressive multifocal leukoencephalopathy (PML). The guidelines include new recommendations on discontinuation of primary and secondary prophylaxis of OIs in children on ART.

Dr Bartlett stated that the revision of the Guidelines for the Use of Antiretroviral Agents in HIV-1- Infected Adults and Adolescents was released on November 3, 2008. The revision includes a new section on treatment simplification in virologically suppressed patients; a change in the threshold of HIV/RNA levels at which resistance testing may be considered; and a new rating system for Strength of Recommendations and Quality of Evidence. He stated that the Working Group will review the impact on these guidelines of two recent observational cohort trials: the When to Start Consortium and the North American ACCORD Study. Dr. Bartlett stated that the Working Group also will begin updates of other guidelines for adults, such as guidelines for HIV prevention, Hepatitis C, etc.

Dr. Bartlett reported that revisions to the Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States will be released in April 2009. The revised guidelines will address updated recommendations on the use of antiretrovirals (ARVs) during pregnancy and HIV transmission via breastfeeding.

Dr. Bartlett stated that the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection were released on February 23, 2009. The revisions address ARV treatment failure in children and ARV drug resistance testing, drug dosing, and a pediatric ARV drug information supplement.

Dr. Bartlett acknowledged the more than 250 Working Group members who have contributed to the recent guidelines updates.

Introduction of Topic

Dr. Curran asked Dr. Gina Brown, OAR, to introduce the topic of the meeting: HIV Prevention Research for Women. Dr. Brown stated that as HIV/AIDS increasingly becomes a women’s epidemic, issues of risk and prevention have become more complex. She discussed the need to review the multi-factorial issues that impact risk and the need for complex prevention strategies. She noted that HIV research is addressing questions about the biology and immunology of HIV risk, the role of the female genital tract in HIV risk, and how to leverage innate physiology to address issues of prevention.

Dr. Brown stated that the successful development of HIV prevention strategies will be impacted by behavior, social, cultural, and biological issues, as has proven true for existing HIV treatment approaches. Dr. Brown noted that the meeting presentations would address the complicated issues of HIV risk for women and generate discussions about how to better address prevention research, including the integration of biomedical and behavioral strategies.

Dr. Curran stated that this meeting represents an opportunity to prioritize HIV prevention research in women. He noted the Council’s interest in hearing the participants’ recommendations, comments, and discussion.

HIV in Women in the United States and Internationally

Dr. Jessica Justman, Columbia University, presented an overview of trends in the HIV epidemic in women. She cited recent statistics from the Joint United Nations Programme on HIV/AIDS (UNAIDS) which show an increase in the global HIV epidemic in women, especially in Sub-Saharan Africa. She noted that the HIV epidemic has affected women in some regions to a lesser extent than in other parts of the world, with HIV prevalence rates still higher in young women compared to young men in several Sub-Saharan African countries.

Dr. Justman stated that UNAIDS statistics show that the HIV epidemic in Asia and Latin America tends to be more concentrated among commercial sex workers, injection drug users, and men who have sex with men (MSM). There appears to be a general increase in self-reporting of condom use in these regions. UNAIDS statistics also show that only about 30 percent of HIV sero-positive pregnant women worldwide are receiving ART prophylaxis for prevention of mother-to-child transmission of HIV (PMTCT). However, there has been an encouraging trend toward increased use of ART prophylaxis in this population. UNAIDS also reports a downward trend in deaths due to AIDS worldwide over the past several years.

Dr. Justman summarized domestic trends in HIV incidence and mortality based on recent CDC statistics. She noted that HIV incidence peaked in the United States at about 140,000 cases per year in the mid 1980s, declined through the late 1990s, and stabilized at current rates of about 56,000 cases per year. Dr. Justman stated that about 15,000 new HIV infections occur in women in the United States each year. HIV incidence and mortality rates are highest for black women compared with white or Hispanic women. Non-Hispanic white women have the lowest HIV mortality rates.

Dr. Justman commented on a meta-analysis of 43 observational studies on HIV transmission. The data showed the probability of female-to-male HIV transmission per sex act is about half that of male-to-female transmission rates in high income countries. Although overall transmission rates are much higher in lower income countries, the rates for female-to-male and male-to-female transmission are similar. Dr. Justman stated that in contrast to global trends for new HIV cases in women, U.S. trends show little progress. She noted the need to identify how much of the epidemic is affected by behavior versus biology and the need to focus both on HIV treatment and prevention.

Immunology and the Female Genital Tract

Dr. Charles Wira, Dartmouth Medical Center, described how the regulation of the immune system in the female reproductive tract (FRT) impacts the risk for HIV infection. He stated that studies using radiopaque dyes showed that the upper reproductive tract is not isolated from the lower reproductive tract. He noted that pathogens, as well as sperm, are able to move from the vagina to the cervix, uterus, and fallopian tubes within minutes at all stages of the menstrual cycle. He also stated that FRT immune secretions are directional and move from the upper to the lower tract with innate and adaptive immunity existing throughout the entire FRT. Estradiol and progesterone regulate the changes in the immune system that occur throughout the menstrual cycle.

Dr. Wira and his colleagues have reported that a window of vulnerability to HIV and other sexually transmitted infections (STIs) begins at ovulation, lasts for 7 to 10 days, and is linked to mid-cycle rises in estradiol and progesterone. During this time, the immune system of the FRT is suppressed to allow fertilization and implantation of an embryo. He commented that the immune systems of both the upper and lower female genital tracts are affected during this window of vulnerability, but in different ways. In the uterus, the adaptive immune system is suppressed at the time of ovulation, while the innate immune system is enhanced through secretions of immunologic antimicrobials. In the lower FRT, the innate immune system is suppressed at the time of ovulation by decreased antimicrobial secretions, while the adaptive immune system is not affected.

Dr. Wira cited research findings that show HIV is transmitted via a single infectious unit in 80 percent of male-to-female or male-to-male HIV infections, although semen contains millions of virions. The other 20 percent of infections involve from two to six infectious units. He also described in vitro studies exploring the inhibition of HIV infectiousness by cervical/vaginal lavage fluid, which contains antimicrobial secretions.

Dr. Wira summarized that the FRT experiences a window of vulnerability as a result of changing hormonal levels and suppression of humoral, cell-mediated, and innate immunity. He stated that studies which focus on controlling this window of vulnerability will be important to better understand how HIV is transmitted and the development of new approaches to HIV prevention. He proposed additional research was needed on agents which have selective differential effects on cellular estradiol, such as selective estrogen receptor modulators (SERMs), to mediate this window of vulnerability.

Mucosal Immunity in the Gastrointestinal and Genital Tracts and Vaccines that Prevent Transmission

Dr. Jiri Mestecky, University of Alabama at Birmingham, presented on the importance of the mucosal immune system of the genital tract in HIV infection. He stated that 90 percent of HIV infections occur through the mucosal surfaces of the genital or gastrointestinal (GI) tracts. He noted that the differences between vaginal and GI mucosal immunity must be considered in the design and development of vaccines.

Dr. Mestecky noted that his research on humoral immune responses to HIV infection demonstrates an increased role of IgG antibodies compared with IgA antibodies in serum, rectal fluid, cervicovaginal fluid, seminal plasma, and peripheral blood. These studies also provide evidence for the dependence of the vaginal tract on the systemic adaptive immune system in response to exposure to various pathogens either though infection or immunization.

Dr. Mestecky described future directions for research in this area, including studies on: 1) standardized approaches to evaluate the humoral and cellular responses in external secretions of the genital tract in the evaluation of HIV vaccines; 2) the effectiveness of systemic immunization in protection of the female and male genital tracts; 3) the effectiveness of immunization (including intranasal and sublingual routes) in humans for the induction of immune responses in female and male genital tracts; 4) mechanisms of extracellular and intracellular antibody-mediated protection; and 5) whether vaginal-uterine exposure to antigens induce mucosal tolerance.

Vaginal Mircoflora Risk and Prevention

Dr. Jared Baeten, University of Washington, discussed the influence of the vaginal microflora on HIV risk and prevention. He noted that the normal vaginal environment is dominated by Lactobacillus species which produce lactic acid, hydrogen peroxide, and other factors that likely are protective against invasive pathogens, including HIV. In contrast, the vaginal ecosystem is out of balance in bacterial vaginosis (BV), with an overgrowth of anaerobic flora and a reduction in Lactobacillus. Dr. Baeten stated that since abnormal vaginal flora is common in areas of the world where HIV is highly prevalent, this could translate into a large population-attributable risk.

Dr. Baeten noted that ulcerative STIs have long been known to increase HIV susceptibility. He reviewed more recent evidence that non-ulcerative STIs may heighten HIV susceptibility.

Dr. Baeten’s findings from a prospective cohort of female commercial sex workers attending a clinic in Mombasa, Kenya showed that BV and vaginal candidiasis are independently associated with increased risk of HIV acquisition. Possible biologic mechanisms for this effect include decreased Lactobacillus colonization, immunologic effects of various mucosal cytokines, and/or the effects of opportunistic STIs.

Dr. Baeten discussed the possible association of vaginal washing, BV, and HIV risk. He noted that vaginal washing is common in populations worldwide, particularly where HIV infection is highly prevalent. Data from the Mombasa cohort showed a clear relationship between vaginal washing and HIV risk, although not all studies on this topic have found the same association. Dr. Baeten discussed three possible mechanisms for vaginal washing and increased HIV risk: direct mucosal disruption; recruitment of target cells; and alteration of vaginal pH.

Dr. Baeten presented findings showing the spectrum of bacterial diversity in the genital tract is radically expanded in women with BV. Some of these bacteria were associated with BV treatment failure. Dr. Baeten listed five possible intervention strategies for BV that may address this problem: increased microbial surveillance, specific diagnosis, and directed treatment; syndromic management of women with vaginal itching and discharge; periodic presumptive treatment; vaginal flora reconstitution with Lactobacillus; and behavioral interventions to modify vaginal practices.

Dr. Baeten stated that findings from a randomized clinical trial of periodic presumptive treatment with oral antibiotics for BV in the Mombasa cohort were encouraging, but not sufficient to warrant a large HIV prevention trial. He noted that the Sexually Transmitted Infections Clinical Trials Group is developing a protocol for other possible intervention strategies. Dr. Baeten noted that the development of interventions to improve vaginal health can provide an important female-centered and female-controlled HIV prevention strategy.

Discussion Session I

OARAC members and presenters discussed the topics presented by Drs. Justman, Wira, Mestecky, and Baeten. Discussion addressed the effects of lifetime hormonal changes, pregnancy, and the use of hormonal contraceptives on the risk of HIV acquisition; the role of epithelial cells in HIV infection; HIV transmission in women and PMTCT; the effect of immune responses in the genital tract on vaccine efficacy; the impact of STI and vaginal flora on global and international racial disparities for HIV acquisition and transmission; and the contribution of behavior, education, and sexual networks on recent declines in HIV prevalence in Africa.

The Role of Hormones in HIV Risk and Prevention

Dr. Charles Morrison, Family Health International, provided an overview of current research on the role of hormones in HIV risk and prevention. Dr. Morrison stated that hormonal contraceptives (HCs) are used by over 150 million women worldwide, with over 100 million using combined oral contraceptives (COCs) and more than 50 million using depot-medroxyprogesterone acetate (DMPA) injections. Use of DMPA and other injectable progestins is increasing rapidly, especially among young women and in Southern Africa.

Dr. Morrison described several possible biologic mechanisms by which use of HC may increase risk for HIV acquisition. He noted that, of all prospective studies on the use of HCs and HIV risk, those that have focused on women at low risk for HIV acquisition tend to find no increase in risk, or lower risk in women using COCs or DMPA. In contrast, studies that focused on women in higher HIV risk populations tended to find an increased risk for HIV acquisition with use of COCs or DMPA.

Dr. Morrison outlined the findings from two large prospective studies on this topic. The Hormonal Contraceptive and the Risk of Acquisition (HC-HIV) Study was conducted in Uganda, Zimbabwe, and Thailand, among 6,000 HIV-uninfected women ages 18 to 35. In this study, neither COCs nor DMPA use was associated with a statistically significant increase in risk for HIV acquisition. The second study, the Mombasa Sex Worker Study followed about 1,300 commercial sex workers for a median of 16 months. DMPA and COC use were both associated with an increased risk of HIV acquisition.

Dr. Morrison stated that a priori analysis of HC-HIV data showed that neither vaginal nor cervical infections modified the relationship between the use of HCs and HIV risk. However, there was an age-dependent association between negative status for herpes simplex virus-2 (HSV-2) at the time of enrollment, HC use, and HIV risk. Among HSV-2 negative women, the use of HC was associated with increased risk for HIV acquisition in women aged 18 to 24, but it was protective in women age 25 and older. Among women aged 18-24, the youngest women had the highest risk for HIV acquisition with HC use. Dr. Morrison also noted a slight, but not statistically significant trend for an HC/HIV/HSV-2 age effect in the Carreguard Microbicide Trial. Although the Mombasa study showed no HC/HIV/HSV-2 effect, the sample size for HSV-2 negative women was small in this study.

Dr. Morrison summarized the research priorities for hormonal contraception and HIV-1 acquisition from the World Health Organization (WHO) Technical Meeting held in Geneva, March 13-15, 2007. These priorities underscore the importance of more basic, clinical, and translational research in this area.

Norms of Sexual Behavior and Risk in Women

Dr. Shari Dworkin, University of California, San Francisco, described research trends in the norms of behavior related to HIV risk in women. She noted that 80 percent of HIV infections in women in the United States are acquired through high-risk heterosexual contact. She stated that HIV prevention intervention strategies are transitioning from gender-neutral to gender-sensitive and gender-transformative (also called structural) approaches. She noted that social science in the future will need to consider how to operationalize and measure the impact of gender norms on HIV risk. She stated that the dyadic nature of sex requires consideration of masculinity, as well as femininity, in the development of gender-sensitive and gender-transformative HIV prevention interventions. She also noted the importance of couples-level interventions.

Dr. Dworkin reviewed two randomized controlled trials (RCTs) on gender-sensitive and gender-transformative HIV prevention interventions. In the first trial, Project Connect, an intervention which emphasized gender norms was as efficacious when presented to couples as when it was presented to women alone. The second trial, Project FIO (the Future Is Ours) seeks to reduce the sexual risk behaviors of heterosexual urban women in New York City. The study enrolled a disproportionate number of racial and-ethnic minorities. The intervention addressed gender and sexual norms, including feminine passivity; safer sex skills; the right of women to prioritize their own sexual needs and desires; and the right to say “no.” Dr. Dworkin stated that Project FIO is one of the longest running successful gender-specific interventions with significant outcomes at one year.

Dr. Dworkin described several metanalyses and literature reviews on gender-transformative interventions addressing factors such as power, gender, age-relations, and poverty. She presented findings from the prospective RCT-Intervention with Microfinance for AIDS and Gender Equity (IMAGE). This community-matched intervention trial based in rural Limpopo in South Africa showed significant reductions in violence and significant improvements in safer sex behaviors with a non-spousal partner after the intervention, although HIV incidence was not impacted. Another study showed improvements in housing stability can substantially reduce HIV risk. Dr. Dworkin emphasized the need to integrate HIV prevention, treatment, and care with other services, such as family planning.

Dr. Dworkin identified several research needs, including studies on: norms of sexual behavior and HIV risk in women; basic social and behavioral sciences to design better interventions that take into account unique gender and sexuality norms; gender-sensitive and gender-transformative HIV prevention interventions; heterosexually-active men domestically; structural-level integrations of HIV prevention and economic empowerment; and integration of anti-violence/HIV prevention services.

Sexual Networks and HIV Risk in Women

Dr. Adaora Adimora, University of North Carolina, discussed the role of sexual networks in HIV risk in women. Dr. Adimora defined “concurrency” as sexual partnerships that overlap in time. Concurrency supports a more rapid spread of HIV and other STIs among a population. “Direct concurrency” applies to individuals who have concurrent partnerships and is associated with increased risk of HIV transmission. “Indirect concurrency” applies to individuals who have partners who have concurrent partnerships with other individuals. Indirect concurrency is associated with increased risk for HIV and other STIs.

Dr. Adimora discussed findings related to concurrency from the 2002 National Survey of Family Growth (NSFG). She noted that 84 percent of men in this survey had no more than one sexual partner in the past year and the prevalence of concurrency in men was about 11 percent. The number of men with concurrency who reported having a non-monogamous female partner was also about 11 percent. The demographic correlates of concurrency for men were young age, being unmarried, earlier age at first sex, lack of condom use, general risky behavior, and higher income. The behavioral correlates of concurrency included recent incarceration, use of drugs or alcohol during sex, MSM, and belief that a female partner has been non-monogamous. Men with concurrency were twice as likely to have not used condoms with any partners at last sex compared to men without concurrency. The survey showed an increase in the lack of condom use over time with concurrency. Dr. Adimora stated that these associations highlight the existence of densely interconnected networks, and bridging between women and bisexual men.

The survey findings for women showed 89 percent of women had no more than one partner during the past 12 months. Black women were more likely to have had zero partners compared with white women. White women were most likely and Hispanic women least likely to have had 11 or more partners over their lifetime. The number of women with concurrency who reported having a non-monogamous male partner was about 9 percent, with the highest rates among black women. The demographic characteristics of concurrency among women were black race, age (highest rates at ages 30-34), being unmarried, and earlier age at first sex. The behavioral correlates of concurrency for women were the use of drugs or alcohol during sex, binge alcohol consumption, crack or cocaine use, and the belief that a male partner is non-monogamous.

Dr. Adimora described sexual mixing patterns and HIV risk. She defined “assortative mixing” as partnerships between people who have a similar risk for HIV infection or STIs. Assortative mixing keeps infection within the risk subpopulation. She defined “dissortative mixing” as occurring when individuals from high and low risk categories form partnerships. This type of mixing disseminates infection throughout the population. She noted that social and sexual networks are typically assortative and sexual networks are relatively segregated by race. She presented data showing more frequent dissortative mixing among African American women than among white or Hispanic women.

Dr. Adimora concluded that HIV interventions should consider the influence of networks on population level HIV transmission; individual risk of acquiring and transmitting HIV; and factors that influence networks.

Discussion Session II

OARAC members and presenters discussed the presentations by Drs. Morrison, Dworkin, and Adimora. They addressed the importance of the dyadic nature of sexual interaction; the influence of factors of masculinity on women’s risk for HIV; the role of gender-transformative interventions, gender norms, and gender equity; and the role of gender empowerment in increasing condom use. The discussion also emphasized the role of direct and indirect communication in condom use; dual use of HCs and condoms; and the potential causes of increased risk of HIV acquisition in young women who use HCs. OARAC members commented on the need for the integration of HIV, STI, and family planning services; the crucial role of HIV testing in HIV prevention and the cost of testing; the importance of having an integrated system to refer individuals who test HIV sero-positive to care; and barriers to the availability of condoms.

Role of Fertility ad HIV Risk

Dr. Susan Allen, Emory University, presented an overview of the role of fertility and HIV risk with a focus on African couples. She described data showing that in urban and, especially, rural settings in Africa, most adults are in cohabiting unions and most sexual encounters and HIV transmissions occur in this setting. She also noted the relevance of the dyadic component of HIV transmission in high risk populations in the United States and Europe, where 68 percent of new HIV infections in MSM are acquired from steady partners.

Dr. Allen reviewed some of the myths and realities of sex, violence, and fertility in Africa. She stated that myths include the perception that Africans have many sex partners, men are abusive and women are powerless; behavior change interventions have no impact; and couples are staunchly pro-natalist. She also stated that, in fact, Americans have more sex partners than Africans and have the same prevalence for intimate partner violence; couples HIV testing and counseling (CVCT) reduces HIV incidence in co-habiting couples in Africa; and pregnancy incidence declines when modern contraceptives are provided. Dr. Allen presented evidence supporting the need for HIV prevention interventions that view co-habiting African couples as a collaborative unit. She stated that HIV sero-concordant couples also benefit from CVCT. She suggested that most new HIV infections in African cities could be prevented by CVCT.

Dr. Allen summarized data on hormonal contraceptive (HC) use in HIV sero-discordant couples. She stated that the use of HCs was not associated with reduced condom use, increased seroconversion in HIV uninfected or sero-negative women, increased HIV transmission from women-to-men, or mortality in HIV sero-positive women.

Dr. Allen suggested new research paradigms for HIV prevention, including analysis of dyads rather than individuals in international and domestic research; methods that prevent both HIV acquisition and transmission and pregnancy; and behavioral, social, and programmatic research to optimize integrated HIV prevention and family planning service delivery.

Social Unrest and HIV Risk

Ms. Jennifer Klot, Social Science Research Council, discussed the effects of sociopolitical factors on HIV risk in women. Ms. Klot stated that military conflict has been a factor driving the HIV/AIDS epidemic in some parts of the world and that post conflict periods can carry even greater risks for HIV transmission in some settings. She noted that the impact of social unrest on the HIV epidemic will vary depending on the country affected and the cause of the unrest.

Ms. Klot outlined four variables that significantly influence the link between the HIV epidemic and security: pre emergency prevalence of HIV; the level of infrastructure for healthcare, transportation, and other services; population movement; and the role of sexual violence, sexual exploitation, and sex for survival. Ms. Klot highlighted possible linkages between HIV/AIDS prevalence and the magnitude of the conflict; transit routes and migration patterns during conflict; and drug trafficking patterns. She stated that HIV/AIDS disproportionately impacts women and girls in countries affected by conflict. Ms. Klot noted disclaimers about the difficulty of obtaining surveillance data during conflict situations.

Ms. Klot stated that biological and social factors of sexual violence are underrepresented in epidemiological and behavioral models of HIV transmission risk. She suggested that sexual violence may partly explain the dissonance between the view of HIV as a heterosexual pandemic in Africa and the limited impact of interventions targeting this population. In particular, sexual violence may contribute to the disproportionate rates of infection in young women. Ms. Klot reviewed indicators of sexual violence in Africa.

Ms. Klot described research using “core group theory,” where individuals at high risk for HIV, e.g. sex workers, constitute the core group. The individuals who interact sexually with the core group comprise the peripheral group.

Ms. Klot concluded with the need to consider the effects of various types of social unrest on HIV risk. She and her colleagues are working to develop a better definition of “risk group” and are conceptualizing frameworks to explain HIV/AIDS-related sexual violence; design appropriate measurement tools and indicators; and reassess provision, access, and utilization issues for HIV prevention services in settings affected by conflict.

Discussion Session III

OARAC members and presenters discussed the two previous presentations. They addressed the role of violence in HIV transmission; population growth as a public health issue; and the need for family planning services in developing countries.

Behavioral Interventions: What Works

Dr. Dolores Albarracín, University of Illinois at Urbana Champaign, presented on the effectiveness of various behavioral interventions for HIV prevention in women. She stated that the determinants of the success of one intervention relative to another are not well understood. She defined three stages of the intervention process: enrollment, completion, and behavior change.

Dr. Albarracín presented findings from two metanalyses on interventions that promote the use of condoms. The analyses showed no statistically significant differences in the odds ratio for enrollment of men and women into the programs. However, the odds ratios for completion of the intervention were significantly lower for women. Women also changed their behavior less in response to these programs. Dr. Albarracín noted that this same bias is seen in the gender imbalance of HIV infection rates.

Dr. Albarracín described a field study of spontaneous information-seeking behaviors in a waiting room type setting. The study showed that women were most likely to read a brochure targeted to women, although women also read brochures that were targeted to men or were gender neutral. Dr. Albarracín noted that men tend to read brochures targeted to men, will read gender neutral brochures, but they will avoid brochures that target women.

Dr. Albarracín outlined research findings showing that women are more motivated to complete an intervention that provides support through connection to a group. In contrast, men were less likely to complete an intervention that involved group support, but they were motivated by monetary payment or provision of healthcare.

Dr. Albarracín described a field study on the efficacy of HIV prevention interventions in changing behavior. Findings from this study showed that men who were trained in the use of condoms were more likely to use condoms than men who did not receive this training. In contrast, women who were trained in condom use were less likely to use them than their untrained counterparts. Dr. Albarracín noted that interventions to teach women interpersonal skills also decreased condom use overall. Since condom training sessions are a common HIV prevention intervention for women and men, these findings need to be taken into consideration in developing better prevention interventions.

Dr. Albarracín presented data showing that for all age groups, except teenagers, interventions were more effective when delivered by medical professionals or a professional counselor than when these interventions were delivered by lay community members. Women responded better if the intervention was delivered by a professional of the same gender and/or ethnicity. For teenagers of both genders, the effectiveness of the intervention was similar whether it was presented by professionals or lay community members. Dr. Albarracín concluded her presentation by emphasizing the importance of matching the gender and the race/ethnicity of the instructor with the targeted population for greater effectiveness of the intervention.

Lesson Learned from Phase III Microbicide Trials

Dr. Lut Van Damme, Family Health International, provided an overview of completed or ongoing HIV prevention trials and discussed the lessons learned from phase III microbicide trials. She reported that eight HIV prevention trials completed since 2006 either showed a negative effect or the lack of a positive effect of the intervention. She stated that three completed trials showed a positive effect of the intervention or positive data from a safety perspective. These three studies include the first pre-exposure prophylaxis (PrEP) trial to be completed and the HIV Prevention Trials Network (HPTN) 035 trial, which evaluated the safety and efficacy of two vaginal microbicide candidates.

Dr. Van Damme discussed general lessons learned from biomedical HIV prevention research. She stated that the boundaries are fading between HIV prevention trials; communication among trials and among Independent Data Monitoring Committees is crucial; and trials are successful if they have met their objective, independent of the results. She noted that research in this field has demonstrated that HIV prevention trials can be successfully conducted.

Dr. Van Damme also described the lessons learned from phase III vaginal microbicide trials. She stated that adherence rates to microbicide trials have been low, but are improving. Low adherence decreases the statistical power of a trial to detect an effect from the intervention. Efforts to improve adherence include intensive and repeated training of staff; counseling of participants; real-time data assessment; tests to confirm use of the microbicide applicator; and microbicide application methods that are not linked to the sex act. Potential long term strategies in microbicide research include the development of biomarkers to document product use and HIV exposure; pharmacologic data to verify product use; and long-acting microbicide candidates.

Dr. Van Damme noted that the use of finger prints, retina photographs, and ID cards may be useful in avoiding co-enrollment of individuals in more than one microbicide clinical trial. Other approaches include careful assessment at screening and enrollment, as well as training of clinical trial site staff and study participants about the potential dangers of co-enrollment. Despite these precautions it may not be possible to completely avoid co-enrollment of study participants in more than one clinical study at the same time.

Dr. Van Damme noted that since women who become pregnant during a microbicide trial generally are taken off the product, but are included in follow-up, pregnancy has the same effect as low adherence in reducing the statistical power of the trial. Required use of contraception; training of staff; and improved access to intrauterine devices (IUDs) are strategies to reduce pregnancy rates in microbicide trials. The Microbicide Trials Network (MTN) is performing one small study to test the safety of microbicide use in pregnancy. The MTN also has established a registry for data on pregnancies that occur during biomedical HIV prevention trials.

Dr. Van Damme described several strategies to improve retention rates in phase III microbicide trials, including the provision of medical care, maintenance of good rapport with the study participants, and counseling on the need for high retention. She noted it also is helpful to have flexible clinic hours; reminder calls to study participants; immediate tracking after a missed visit; the provision of meals and/or childcare during visits; and the sharing of experiences across study sites. Many investigators are soliciting the assistance of behavioral and social scientists to improve the retention of study participants in these clinical trials.

Dr. Van Damme noted that several microbicide trials have had to close due to a lower incidence of HIV in the study population than originally predicted. She concluded her presentation by underscoring the importance of microbicide research as an important component of the prevention agenda.

Discussion Session IV

OARAC members and presenters discussed the presentations of Drs. Albarracín and Van Damme. They addressed the duration of behavioral change following HIV prevention interventions; the impact of the sources of information on behavior change in adolescents; and lessons learned about the biology of agents used in HIV prevention clinical trials. The OARAC members noted the need for new, better formulated drugs and microbicide candidates; better biomarkers; better clinical assays; and improved coordination among microbicide research trials.

Discussion of Recommendations from the Council

Dr. Curran led a discussion to formulate recommendations on HIV prevention research in women. Several themes emerged during the discussion:

• HIV prevention research in women that considers the dyadic nature of HIV transmission, with a focus on cohabiting couples, premarital couples, and individuals before sexual debut. This perspective includes the need for gender-transformative interventions and an understanding of the role of both masculinity and femininity in HIV transmission risk in the United States and globally;

• research on mucosal immunity, physiology, and HIV pathology of the female reproductive tract;

• development of microbicides that could be effective against HIV and other STDs that could also be used as a contraceptive; need for better animal models and pre-clinical testing of potential microbicidal agents;

• research on the effects of hormones on genital mucosal immunity in women of various age groups;

• additional emphasis on biology and behavior research in adolescents;

• use of resources that were created for the development of HIV treatment drugs to enhance the development of drugs for HIV prevention;

• integration of research on HIV prevention, STI prevention, family planning, and reproductive health;

• basic and clinical research on behavioral issues which may affect the success of multi-behavioral prevention interventions;

• dyadic-focused, culturally-tailored strategies to reduce HIV mortality rates among women in racial and ethnic populations in the United States;

• networks for HIV prevention research among women in racial and ethnic populations to prevent increases in HIV prevalence in this population;

• research to empower women to use condoms and microbicides to prevent HIV transmission;

• behavior or policy research to determine barriers to the implementation of proven interventions; and

• research on methodologies for assessing the efficacy of structural interventions.

PUBLIC COMMENTS

No members of the public requested time to comment.

ADJOURNMENT

Dr. Curran thanked the OARAC members, speakers, and guests for their participation. He also thanked Dr. Whitescarver, Dr. Brown, and OAR staff. Dr. Whitescarver thanked Dr. Curran for moderating a very complex and comprehensive agenda.

The meeting adjourned at 4:30 p.m. on April 23, 2009.

Signed:

/Jack Whitescarver, Ph.D./
Jack Whitescarver, Ph.D., Executive Secretary

/James W. Curran, M.D., M.P.H./
James W. Curran, M.D., M.P.H., Chair